Better outcome of HBe Ag(-) than HBe Ag(+) lamivudine treatment of HBV chronically infected patients - Epidemiological Review

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Problemy zakażeń

STRESZCZENIE

Od maja 2006 do grudnia 2007 w Oddziale Dzien-nym Wojewódzkiego Szpitala Zakaźnego leczono lamiwudyną 108 pacjentów z pzw typu B. Obecność antygenu HBe potwierdzono u 46 (42.5%), a u 62 (57, 5%) antygen HBe był nieobecny. Wysokość wiremii HBV analizowano kolejno w 24, 48 i 72 tygodniu terapii stosując metodę Real Time HBV PCR firmy Abbott z limitem czułości metody 28 kopii/ml. Odpowiedź pełną na leczenie definiowano, jako obniżenie HBV DNA poniżej 102_{kopii/ml (Grupa A). Odpowiedź niepełną}

definiowano, jako utrzymywanie się wiremii w grani-cach 102_-105 _{kopii/ml (grupa B), a brak skuteczności}

leczenia, jako utrzymywanie się HBV DNA powyżej 105 _{kopii/ml (grupa C).}

W świetle dotychczasowych naszych wyników pacjenci HBe Ag (-) wydają się odpowiadać lepiej na leczenie lamiwudyną niż HBe Ag (+).

ABSTRACT

From May 2006 to December 2007 in Warsaw Hospital for Infectious Diseases one hundred and eight patients chronically infected HBV were treated with lamivudine.

Among them 46 (42.5%) were HBeAg (+) and 62 (57.5%) HBeAg (-). HBV DNA levels were analysed in weeks 24, 48 and 72 of therapy using Real Time HBV PCR (Abbott) with a limit of detection of 28 copies/ml. Complete response for treatment was defined as HBV VL of less than 102_{copies/ml (group A). Partial response}

was defined as HBV VL ranging from 102_{to 10}5

cop-ies/ml (group B), and treatment failure was determined by HBV VL above 105_{copies/ml (group C). Presented}

results confirmed better response to lamivudine treat-ment in patients HBeAg (-) than HBeAg (+).

Słowa kluczowe: przewlekle zapalenie wątroby typu B, HBeAg (+), HBeAg (-), przewlekłe leczenie lamiwudyną, różne fazy choroby

Key words: chronic hepatitis, HBeAg(+), HBeAg(-), lami-vudine treatment, distinct phases of diseases

Anna Kołakowska-Rządzka1_{, Hanna Berak}1_{, Janusz Stańczak}2_{, Tomasz Dyda}2_{, Andrzej Horban}1,3

BEttEr oUtComE oF HBe Ag (-) tHAn HBe Ag (+) LAmIVUDInE

trEAtmEnt oF HBV CHronICALLY InFECtED PAtIEntS

WYŻSZA SKUTECZNOŚĆ LECZENIA PACJENTÓW Z PRZEWLEKŁYM

WIRUSOWYM ZAPALENIEM WĄTROBY HBe Ag (-) NIŻ HBe Ag (+)

1 _{Oddział Dzienny, Wojewódzki}_{Szpital Zakaźny w Warszawie}

2 _{Pracownia Diagnostyki Molekularnej, Wojewódzki Szpital Zakaźny w Warszawie} 3_{Klinika Chorób Zakaźnych dla Dorosłych, Warszawski Uniwersytet Medyczny}

INTRODUCTION

In many countries, not only in Asia but also in Cen-tral and Eastern Europe including Poland lamivudine is still therapeutic standard for hepatitis B treatment in naive patients. The availability and low costs of therapy determined such an approach.

Long-term treatment with lamivudine is associated with drug – resistant mutants in as many as 70% of patients after 5 years of therapy (1).

The recent studies have shown better response for antiviral therapy in HBeAg negative than positive patients (2). Most of these data is coming from Asia, or from group of patients with minority of Caucasian race (3,4).The results of treatment of Polish patients are presented rarely. (5,6) .

MATERIALS AND METHODS

From May 2006 to December 2007 in Warsaw Hospital for Infectious Diseases one hundred and eight patients were treated with lamivudine. Among them 46 (42.5%) were HBeAg (+) and 62 (57.5%) HBeAg (-). The response rate was analyzed.

Patients were included to treatment, when met the criteria: chronic HBV infection, elevated ALAT, HBV level > 105 _{copies/ml for HBe Ag (+) and > 10}4 _for

HBe Ag (-) (7). Serum HBe antigens and antibodies was measured using immunoassays by Vitros Immu-nodiagnostic as a standard procedures with sensitivity < 0,35j/ml and specificity about 99,84%.

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Anna Kołakowska-Rządzka, Hanna Berak i inni

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HBV DNA levels were quantified in weeks 24, 48 and 72 of therapy using Real Time HBV PCR (Abbott) with a limit of detection of 28 copies/ml.

Complete response for treatment was defined as HBV VL of less than 102_{copies/ml (group A). Partial response}

was defined as HBV VL ranging from 102_{to 10}5_copies/

ml (group B), and treatment failure was determined by HBV VL above 105_{copies/ml (group C) (8,9).}

RESULTS

Different response for treatment was found in HBe-Ag positive and negative variants. (table 1.)

Among HBeAg (+) patients: After 24 weeks of therapy in the group A there were only 3 patients (6.5 %), 13 pts were in group B (28.3 %) and 30 pts (65.2 %) in group C.

After 48 week 3 (6.5%), 12 (26%) and 31 (67.5%) patients were in groups A, B, C, respectively.

In 72 week of therapy the complete suppression was still observed among 3 pts (6.5%), the partial response only in 5 pts (10.9%), and 38 pts (82,6%) were classified as treatment failure (diagram 1)

Among HBeAg (-) patients: After 24 week of the-rapy complete response was observed in 34 pts (54.5%), partial in 26 pts (41.9%), and only 2 pts (3.2%) did not respond. After week 48 in group A we had already 41 pts (66.1%), group B 20 pts (32.2%), and only 1 pt remains (1.6%) non –responder.

At week 72 in the group A still remains 40 (64.5%) pts, in group B 18 (29%) pts and treatment failure oc-curred in 4(6.5%) of patients (diagram 2).

Differences were statistically significant in respect to HBe Ag (+) and HBeAg (-) patients.

DISCUSSION

Presented results confirmed significant differences in the effectiveness of lamivudine treatment in patients infected with different variants of the HBV virus and in consequence, necessity of different therapeutic appro-ach in these two groups. Despite of identical etiology, HBe Ag (+) and HBeAg (-) variants remain in two distinct phases of disease, so also the response to

tre-atment seems to be different. Lamivudine may still be reasonably chosen for naive patients with HBeAg (-). However, incomplete suppression of virus replication by inadequate drug potency provides opportunity for drug – resistant variants to be selected. Patients with HBeAg (+) should start therapy with more potent drug to avoid selection of compensatory HBV mutations. It is also known (10) that response to alternative antiviral agents is reduced in patients with lamivudine resistant HBV.

ACKnoWLEDGmEntS

This paper was partially granted from Foundation for Research Support, Hospital of Infectious Diseases in Warsaw (HID 022)

REFERENCES

1. Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol 2004; 19: 1276-1282.

2. Zoulim F. Antiviral therapy of chronic Hepatitis B. J Antiv Res 2006; 71: 206-215.

3. Sung Joseph J.Y, Lai Jak-Yiu, Zeuzem S, Lamivudine compared with lamivudine and adefowir dipivoxil for treatment of HBeAg positive chronic hepatitis B. J He-patol 2008; 48: 728-735.

4. Hiromi Yatsuji, Fumitaka Suzuki, Hitom Sezaki, Norio Akuta et al. Low risk of adefovir resistance In lamivu-dine – resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: Two-year follow-up. J Hepatol 2008; 48: 923-931.

5. Berak H, Wasilewski M, Horban A. i in. Ocena skutecz-ności leczenia lamiwudyną przez 48 tygodni pacjentów z przewlekłym wirusowym zapaleniem wątroby typu B HBeAg(+); Przegl. Epidemiol 2006; 60: 253-257. 6. Berak H, Wasilewski M, Horban A i in. Ocena

skutecz-ności leczenia lamiwudyną przez 48 tygodni pacjentów z przewlekłym wirusowym zapaleniem wątroby typu B HBeAg(-); Przegl. Epidemiol 2006; 60: 247-251. 7. European Association for the Study of the Liver. EASL

clinical practice guidelines: management of chronic hepatitis B.J Hepatol 2009; 50:227-242

8. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315-1341

Table 1. Total response for lamivudine treatment Tabela 1. Zbiorcze wyniki leczenia lamiwudyną

Week 24 Week 48 Week 72

HBV DNA <102 ₁₀2_-105 _>105 _<102 ₁₀2_-105 _>105 _<102 ₁₀2_-105 _>105

HBeAg(+)

N= 46 3 (6,5%) 13 (28,3%) 30 (65,2%) 3 (6,5%) 12 (26.0%) 31 (67,5%) 3 (6,5%) 5 (10,9 %) 38 (82,6%) HBeAg(-)

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Lamivudine treatment of HBV ₇₁

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9. Mommeja-Marin H, Monodou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatolgy.2003;37:1309-1319

10. Man-Fung Yuen, Daniel Yee-Tak Fong, Danny Ka-Ho Wong, et al. Hepatitis B Virus DNA Levels at Week 4 of Lamivudine Treatment Predict the 5-Year Ideal Re-sponse. Hepatology 2007; 46 (6): 1695 – 1703. Received: 10.12.2009

Accepted for publication: 26.01.2010 Address for correspondence: Anna Kołakowska- Rządzka, Wojewódzki Szpital Zakaźny 01-201 Warszawa ul.Wolska 37; e-mail: anna.rzadzka@gmail.com

Fig. 2. Response for lamivudine treatment among HBeAg (-) patients

Ryc. 2. Wyniki leczenia lamiwudyną w grupie pacjentów HBeAg (-)

0 5 10 15 20 25 30 35 40 24 48 72 3 3 3 13 12 5 30 ₃₁ 38 pts number weeks HBV DNA <10/2 HBV DNA 10/2-10/5 HBV DNA >10/5

Fig.1 Response for lamivudine treatment among HBeAg (+) patients.

Ryc.1 Wyniki leczenia lamiwudyną w grupie pacjentów HBeAg (+).

0 5 10 15 20 25 30 35 40 45 24 48 72 34 41 40 26 20 18 2 1 4 pts number weeks HBV DNA <10/2 HBV DNA 10/2-10/5 HBV DNA> 10/5

Fig.2 Response for lamivudine treatment among HBeAg (-) patients.

Ryc. 2 Wyniki leczenia lamiwudyną w grupie pacjentów HBeAg (-).

Fig. 1. Response for lamivudine treatment among HBeAg (+) patients Ryc. 1. Wyniki leczenia lamiwudyną w grupie pacjentów HBeAg (+)